EP3558400B1 - Wasserhaltige hydrogele zur wundversorgung - Google Patents

Wasserhaltige hydrogele zur wundversorgung Download PDF

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Publication number
EP3558400B1
EP3558400B1 EP17825217.7A EP17825217A EP3558400B1 EP 3558400 B1 EP3558400 B1 EP 3558400B1 EP 17825217 A EP17825217 A EP 17825217A EP 3558400 B1 EP3558400 B1 EP 3558400B1
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Prior art keywords
wound
layer
hydrogel
terminated prepolymer
weight
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EP17825217.7A
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German (de)
English (en)
French (fr)
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EP3558400A1 (de
Inventor
Markus Kettel
Hanno Richter
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Paul Hartmann AG
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Paul Hartmann AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A61F13/0203—Adhesive bandages or dressings with fluid retention members
    • A61F13/0206—Adhesive bandages or dressings with fluid retention members with absorbent fibrous layers, e.g. woven or non-woven absorbent pads or island dressings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A61F13/0203—Adhesive bandages or dressings with fluid retention members
    • A61F13/0213—Adhesive bandages or dressings with fluid retention members the fluid retention member being a layer of hydrocolloid, gel forming material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052—Mixtures of macromolecular compounds

Definitions

  • the subject matter of the present invention comprises water-containing hydrogels for the treatment of wounds.
  • the healing of skin wounds is based on the skin's ability to regenerate epithelium and connective and supporting tissue.
  • the regeneration itself is characterized by a complex process of interlocking cell activities that gradually advance the healing process.
  • the literature describes three essential healing phases of a wound, particularly in the case of wounds with tissue loss. This includes the inflammatory (inflammatory) or exudative phase for hemostasis and wound cleaning (phase 1, cleaning phase), the proliferative phase for building granulation tissue (phase 2, granulation phase) and the differentiation phase for epithelialization and scar formation (phase 3, epithelialization phase). It has been shown that healing of the wound is particularly promoted by moist wound treatment.
  • wound dressings made of various materials can be used, among other things.
  • necrosis and pathological microorganisms can have a negative effect on the physiological metabolism during the wound healing process. This can often lead to local hypoxia, which can then result in further degradation of the surrounding tissue. This breakdown of the surrounding tissue can, in turn, additionally hinder wound healing, which can lead to chronic wounds.
  • chronic wounds are wounds that do not heal within an expected period of 4 to 6 weeks.
  • the wound is not treated optimally, scars can remain.
  • the affected tissue is only impaired by the scars from a cosmetic point of view, but not in its effectiveness. Otherwise it is also possible that the scarred tissue loses its functional properties, such as its elasticity and sensitivity.
  • Water-based hydrogels are successfully used as a component of wound dressings in the moist treatment of wounds. They are able to absorb exudate emerging from the wound into the gel matrix and to release moisture from the gel matrix, so that the wound is provided with an environment that promotes wound healing. Often they represent the wound contact layers of wound dressings. In the course of the time in which the wound dressings lie on the wound to be treated, the absorption capacity and the moisture release capacity are exhausted, so that the wound dressings containing a water-based hydrogel have to be changed several times until the wound has healed completely .
  • a dressing change represents a critical situation for the patient because the dressing can carry away components of the wound tissue or the sensitive skin surrounding the wound that adhere to the dressing.
  • a composition is advantageous which is able to bind harmful factors in the wound exudate and thus remove them from the wound tissue, as well as to concentrate components of the wound exudate that promote wound healing and thus make them available to the wound tissue in a higher concentration.
  • wound dressings should be comfortable for the patient to wear and restrict the freedom of movement of the affected body parts as little as possible in order not to adversely affect the patient's adherence to therapy.
  • EP630629 discloses water-containing hydrogel matrices comprising a polyurethane-polyurea copolymer and propylene glycol for wound treatment.
  • WO2010 / 000450 and WO2010 / 000451 disclose foam-containing wound dressings with a water-containing hydrogel matrix comprising a polyurethane-polyurea copolymer.
  • EP2338528 and EP2338529 disclose water-containing hydrogel matrices comprising a polyurea-polyurethane copolymer and propylene glycol with improved absorption or adhesive properties.
  • wound healing can still be improved in the above method.
  • constituent propylene glycol has been identified as disadvantageous.
  • the known wound dressings can also lead to skin irritation and can still be optimized with regard to the patient's adherence to therapy.
  • the aim of the present invention is to overcome the disadvantages of the prior art.
  • the object is to provide the use of substances in the treatment of wounds which lead to improved wound healing.
  • the substances or the wound care products containing these substances should be perceived by the patient as pleasant, have good tolerance for wound tissue and skin and lead to advantageous adherence to therapy.
  • This wound care product should be able to be applied as required in all phases of wound healing in order to ensure the above-mentioned effect.
  • a wound is usually present when the tissue connection has been severed on an outer or inner surface of the body.
  • a primarily healing wound is understood to be a wound with non-gaping wound edges, which is characterized by uncomplicated healing without infection. These wounds often occur in parts of the body that are well supplied with blood. The wound edges, which are not gaping and therefore close to one another, may have been caused, for example, by a (surgical) cut. If there is no further treatment, the wound closes without complications. Further wounds are the secondary healing wounds.
  • a secondary healing wound is understood to be a wound if a) there is a loss of tissue and / or b) contamination has occurred which prevents primary healing. The organism can compensate for the loss of tissue through newly formed tissue and skin. In the context of secondary wound healing, this leads to the formation of granulation tissue through to scarred replacement of the tissue gap.
  • the secondary healing wound is a mechanical wound, a thermal wound, a wound caused by chemical substances or by radiation.
  • Mechanical wounds can occur as a result of external violence. These include, for example, cuts, stab wounds, lacerations, bruises, abrasions, scratches, bites and gunshot wounds.
  • Thermal wounds are mainly caused by strong heat or exposure to cold. These include, for example, burns, scalds, frostbite and injuries caused by electrical current.
  • Chemical wounds are burns. These can be caused, for example, by acidic, alkaline, oxidizing and / or reducing substances.
  • Wounds caused by radiation are also known as actinic wounds. These are triggered, for example, by ionizing radiation and can have an appearance similar to burn wounds.
  • Chronic wounds can be defined as wounds whose healing process deviates from normal wound healing in one or all stages of wound healing.
  • Acute, normally healing wounds can develop into a chronic wound, for example due to a wound infection, which is characterized by a delayed healing rate. The transition from an acute to a chronic wound can take place at any stage of wound healing.
  • Clinically, chronic wounds are defined as wounds whose Need more than 6-8 weeks to heal, although this definition does not correctly cover all clinical pictures. Chronic wounds are more of a diagnosis based on the clinical experience of the medical staff.
  • Chronic wounds arise in particular due to mechanical stress (pressure ulcers, pressure ulcers), venous insufficiency (venous leg ulcers, venous ulcers), arteriosclerotic vascular changes (arterial leg ulcers, arterial ulcers), neuropathic changes (diabetic foot syndrome, neuropathic changes Ulcers), but also as a result of autoimmune diseases, tumors (ulcerating tumors) or radiation damage during tumor therapy.
  • the pressure ulcer is defined as trophic disruption of tissues (especially skin and subcutaneous tissue) with necrosis, maceration, possibly infection, caused by external (long-term) pressure with compression of vessels and local ischemia. Decubitus ulcers occur primarily when bedridden, especially on parts of the body where the skin is in direct contact with the bone, but also, for example, under ill-fitting prostheses and casts that are too tight.
  • the pressure ulcer is divided into the following stages. Chronic wounds in particular are level II, level III and level IV pressure ulcers: Pressure ulcer - level I: This is a persistent, circumscribed reddening of the skin that remains even when the pressure is relieved. The reddening is sharply demarcated and can be hardened or overheated. The skin is still intact.
  • Decubitus ulcer - stage II In this phase blistering and abrasion of the skin occur and thus partial loss of the skin. The epidermis up to parts of the dermis is damaged. At this stage there is a superficial wound or shallow ulcer.
  • Decubitus - Stage III In this advanced stage, a loss of all skin layers can already be observed. In addition, damage to the subcutaneous tissue and possibly necrosis can be observed, which can extend to the underlying muscle tissue. Experience has shown that the necrotic tissue must first be delimited before the full extent of the tissue damage can be seen. The pressure ulcer III shows up clinically as an open, deep ulcer.
  • Pressure ulcers - Stage IV In this extremely critical stage, loss of all skin layers with extensive destruction, tissue necrosis or damage to muscles, bones or supporting structures (tendons, joint capsules) is recorded. The pressure ulcer IV shows up clinically as a large, open and deep ulcer.
  • the inflammatory phase usually occurs immediately after the trauma and lasts about three days. It is characterized by vascular contraction, activation of the coagulation cascade and complex immunological processes. As a rule, a fibrin network forms, which closes the wound and protects it from the outside. The release of vasoactive substances (e.g. histamine and serotonin) can cause a local inflammatory reaction.
  • vasoactive substances e.g. histamine and serotonin
  • the surrounding vessels can widen and the increased capillary permeability allows leukocytes to migrate to the site of inflammation. These can eliminate microorganisms and tissue necrosis. This allows the wound to be cleaned.
  • the subsequent proliferation or granulation phase usually begins around the second day after the wound has formed and can last for up to 14 days, for example.
  • New tissue is built up with vascular sprouting and the defect filling with granulation tissue. This is the basic requirement for the subsequent epithelialization.
  • Fibroblasts from the surrounding tissue can migrate into the fibrin network and use it as a temporary matrix.
  • the build-up of collagen fibers begins.
  • the fibrin structure can be broken down by the enzyme plasmin by means of fibrinolysis.
  • the closed vessels can be recanalized.
  • the maturation of the collagen fibers usually begins with the differentiation or remodeling phase, approximately between the sixth and tenth day.
  • the wound contracts by converting fibroblasts into fibrocytes and myofibroblasts. This causes the scar tissue to shrink and the wound to shrink.
  • the epithelialization from the edge of the wound brings the wound healing to a conclusion.
  • the treatment of the wounds is a phase-appropriate wound treatment.
  • phase-appropriate wound therapy is understood to mean that the wound therapy addresses the specific needs of the wound in the individual phases.
  • phase-appropriate treatment can take place in one or more phases of wound healing. (In contrast, with conventional wound treatments, one and the same treatment takes place over all phases).
  • hydrogel denotes a finely dispersed system composed of at least one solid and one liquid phase.
  • This solid phase forms a sponge-like, three-dimensional network, the pores of which are filled with a liquid (lyogel) or a gas (xerogel). Both phases preferably penetrate one another completely.
  • a hydrogel can preferably be constructed from a synthetic or natural material, preferably from a hydrophilic synthetic material.
  • hydrogel is also referred to synonymously below as hydrogel composition or hydrogel matrix.
  • the present invention has a polymer containing polyurethane and polyurea groups as the solid phase.
  • percentages that relate to the concentration of ingredients are understood to denote the proportion of the starting materials mentioned in the overall reaction mixture of prepolymers, water, polyhydric alcohol and, if applicable, salt.
  • Hydrogels which can be used as water-containing hydrogels in connection with the present invention are in particular hydrogels which form a cohesive, discrete layer and do not release any water under a pressure which occurs when the hydrogel is used as intended.
  • the present invention relates to water-containing hydrogels for treating wounds obtainable by reacting a) amine-terminated prepolymer containing polyalkylene oxide units with a b) isocyanate-terminated prepolymer containing polyalkylene oxide units, the reaction being carried out in the presence of a polyhydric alcohol, with the exception of propylene glycol, and in the presence of water takes place and based on the total mass of all reactants the sum of the masses of amine-terminated Prepolymer and isocyanate-terminated prepolymer is 10-30% by weight of the total mass of all reactants and the mass of the polyhydric alcohol, with the exception of propylene glycol, is 5-35% by weight of the total mass of all reactants and the mass of the water used is at least 40% by weight.
  • the molar ratio of reactive isocyanate end groups to reactive amine end groups being 1.0 to 2.0, preferably 1.0 to 1.8, particularly preferably 1.0 to 1.6, very particularly preferably 1.0 to 1.5, most preferably 1.2 to 1.3, characterized in that the polyhydric alcohol is glycerol.
  • the invention relates to a water-containing hydrogel for treating wounds obtainable by reacting a) amine-terminated prepolymer containing polyalkylene oxide units with a b) isocyanate-terminated prepolymer containing polyalkylene oxide units, the reaction being carried out in the presence of a polyhydric alcohol, with the exception of propylene glycol, and takes place in the presence of water and, based on the total mass of all reactants, the sum of the masses of amine-terminated prepolymer and isocyanate-terminated prepolymer is 15-25% by weight of the total mass of all reactants and the mass of the polyhydric alcohol, with the exception of propylene glycol, 5 -35% by weight of the total mass of all reactants and the mass of the water used is at least 40% by weight of the total mass of all reactants, the molar ratio of reactive isocyanate end groups to reactive amine end groups being 1.0 to 2.0, preferably 1.0 to 1.8, particularly preferably 1.0
  • the hydrogel can be obtained by reacting an amine-terminated prepolymer containing polyethylene oxide and / or polypropylene oxide units with an at least three-armed branched isocyanate-terminated prepolymer containing polyethylene oxide and / or polypropylene oxide units in the presence of a polyhydric alcohol, with the exception of propylene glycol, the molar ratio being more reactive Isocyanate end groups to reactive amine end groups 1.0 to 2.0, preferably 1.0 to 1.8, particularly preferably 1.0 to 1.6, very particularly preferably 1.0 to 1.5, most preferably 1.2 to 1 , 3 is.
  • the hydrogel can be obtained by reacting an amine-terminated prepolymer containing polyethylene oxide and polypropylene oxide units with an at least three-armed branched isocyanate-terminated prepolymer containing polyethylene oxide and polypropylene oxide units in the presence of a polyhydric alcohol, with the exception of propylene glycol, the ratio of reactive isocyanate end groups to reactive amine end groups 1.0 to 2.0, preferably 1.0 to 1.8, particularly preferably 1.0 to 1.6, very particularly preferably 1.0 to 1.5, most preferably 1.2 to 1.3 and wherein the weight ratio of polyethylene oxide to polypropylene oxide units both in the amine-terminated prepolymer and in the isocyanate-terminated prepolymer is 3: 1 to 7: 1.
  • a typical amine-terminated prepolymer is, for example, a triblock polymer composed of propylene glycol, ethylene glycol and again propylene glycol units, the polymer being terminally amine-functionalized with 2-aminopropyl groups. It has a content of reactive amine end groups of 0.9554 mmol / g with an average molecular weight of about 2000 g / mol and a dispersity of 1.08, measured by gel permeation chromatography, and a molar ratio of ethylene units to propylene units of 3: 1 to 7: 1, preferably 39: 6.
  • Such an amine-terminated prepolymer is commercially available, for example, as Jeffamin® ED-2003, Huntsman; Everberg, Belgium.
  • a typical isocyanate-terminated prepolymer with aliphatic diisocyanate groups is, for example, a three-armed copolymer of propylene glycol and polyethylene glycol units, each of which has been reacted at the end with a molecule of isophorone diisocyanate. It has a content of reactive isocyanate end groups (NCO groups) of 3.0% to 3.4%, preferably 3.2%, and a molar ratio of ethylene oxide units to propylene oxide units of 3: 1 to 4: 1.
  • NCO groups reactive isocyanate end groups
  • Such an isocyanate-terminated prepolymer with aliphatic diisocyanate groups is commercially available, for example, as Aquapol® PL-13000-3 (Carpenter; Richmond, USA).
  • hydrogel which is obtainable by reacting said amine-terminated prepolymer Jeffamin® ED-2003 with said isocyanate-terminated Aquapol® PL-13000-3 in the presence of a polyhydric alcohol, with the exception of propylene glycol, the mass ratio of Aquapol to Jeffamine is between 1.0 and 2.5, preferably between 1.1 and 1.7.
  • hydrogels are particularly suitable for storing water and delivering this water to a wound.
  • the solid phase is not formed solely by a polymer that results from the reaction between an amine-terminated prepolymer and an isocyanate-terminated prepolymer.
  • a polyhydric alcohol with the exception of propylene glycol, is also involved in the reaction, the free hydroxyl groups of which can react with isocyanate groups.
  • the polyhydric alcohol component contributes to an additional crosslinking which, in particular in the case of polyhydric alcohols with more than two hydroxyl groups, leads to a three-dimensional crosslinking of the prepolymers.
  • the reaction between a polyhydric alcohol and an isocyanate group produces a carbamic acid ester, which is also known as urethane.
  • This reaction can be accelerated by using acids or bases as a catalyst and can be reversed with the addition of thermal energy. If the reaction temperature is kept constant between 5 ° C. and 30 ° C., preferably between 5 ° C. and 20 ° C., this reaction can take place in a sufficient ratio so that hydrogels with covalently bound polyhydric alcohols are obtained which have advantageous properties.
  • Hydrogels according to the invention also contain glycerol.
  • This alcohol is excellently suited as a moisturizer and thus represents a caring component for the skin surrounding the wound.
  • Hydrogels which contain this alcohol as a partner in the reactions described above have a high absorption capacity for wound exudate and a reduced loss of moisture. They have an adhesive force that allows an atraumatic dressing change. Due to their low cytotoxicity, they are very well tolerated by wound tissue. In addition, such gels are able to concentrate the wound exudate growth factors necessary for wound healing and thus accelerate wound healing. This is particularly true for glycerol-containing hydrogels.
  • glycerol is used as the polyhydric alcohol in a concentration of 10-25% by weight.
  • Such hydrogels have particularly advantageous properties with regard to cell compatibility, fluid loss and adhesion.
  • glycerol is used as the polyhydric alcohol in a concentration of 15-25% by weight.
  • Such hydrogels also have a particularly high absorption capacity.
  • a hydrogel according to the invention contains at least 40% by weight and very particularly preferably at least 50% by weight of water, the hydrogel further preferably comprising at most 90% by weight and furthermore preferably at most 80% by weight of water. It is thus possible to provide a hydrogel for wound treatment which provides an amount of moisture sufficient for natural wound healing.
  • the water-containing hydrogel matrix in particular comprises at least one salt.
  • the hydrogel matrix comprises an inorganic salt. Chlorides, iodides, sulfates, hydrogen sulfates, carbonates, hydrogen carbonates, phosphates, dihydrogen phosphates or hydrogen phosphates of the alkali and alkaline earth metals are particularly suitable in this connection.
  • the hydrogel matrix preferably comprises sodium chloride, potassium chloride, magnesium chloride, calcium chloride or mixtures thereof. Sodium chloride is particularly preferred. These salts simulate the electrolyte mixture in a wound serum released by a wound in a particularly good way. A hydrogel matrix comprising these salts thus provides a wound with a climate that is particularly conducive to wound healing.
  • the hydrogel matrix comprises 0 to 5% by weight of at least one salt.
  • the hydrogel matrix comprises 0.1 to 3% by weight of a salt and very particularly preferably 0.5 to 1.5% by weight of a salt.
  • Hydrogels according to the invention are suitable for the treatment of wounds. They can be distributed as semi-solid, plastically deformable masses on a wound surface by means of suitable application devices. Suitable application devices are, for example, tubes or adapted syringes.
  • Hydrogels according to the invention are preferably part of a wound dressing.
  • a wound pad is understood to mean a product which is applied to a wound and is made available in ready-to-use form.
  • Suitable wound dressings have at least one layer made of a carrier material and one layer comprising a hydrogel according to the invention.
  • polymer films or polymer foams can be used as the carrier layer, preferably films or foams made from polyurethane, polyether urethane, polyester urethane, polyether-polyamide copolymers, polyacrylate or polymethacrylate.
  • a water-impermeable and water-vapor-permeable polyurethane film or a water-impermeable and water-vapor-permeable polyurethane foam is suitable as the carrier layer.
  • a polyurethane film, polyester urethane film or polyether urethane film is preferred as the polymer film.
  • polymer films which have a thickness of 15 ⁇ m to 50 ⁇ m, in particular 20 ⁇ m to 40 ⁇ m and very particularly preferably 25 ⁇ m to 30 ⁇ m are also very particularly preferred.
  • the water vapor permeability of the polymer film of the wound dressing is preferably at least 750 g / m 2 / 24h, in particular at least 1000 g / m 2 / 24h and very particularly preferably at least 2000 g / m 2 / 24h (measured according to DIN EN 13726).
  • these films have a moisture-proof, adhesive edge section. This edge section ensures that the wound system can be applied and fixed at its intended location.
  • the absorbent layer comprises a hydrophilic polyurethane foam and the hydrogel.
  • a hydrophilic polyurethane foam can be impregnated or coated with the hydrogel or completely or partially penetrated by this.
  • the hydrogel composition can also be present adjacent to or spatially separated from the absorbent layer.
  • the hydrogel composition for example comprising a polyurethane-polyurea copolymer, can be coated on a surface of a layer of a polyurethane foam so that a hydrogel layer comprising the hydrogel composition rests in direct contact on a layer of polyurethane foam.
  • the hydrogel layer and the absorbent layer can also be separated from one another by a spacer layer.
  • the spacer layer can comprise a hydrogel matrix, a polymer film, a hydrocolloid matrix, a polymer network, a textile fabric, an adhesive and / or a polymer network.
  • the multilayer wound dressing can also comprise further layers in addition to the absorbent layer and the carrier layer, such as, for example, a wound contact layer, one or more barrier layers and / or one or more distribution layers.
  • Preferred wound dressings comprise a carrier layer, a hydrogel layer according to the present invention and, optionally, an absorbent layer arranged between the hydrogel layer and the carrier layer.
  • the absorbent layer can preferably comprise a fiber material, particularly preferably a hydrophilic polyurethane foam.
  • the hydrogel layer can be continuous or discontinuous. It can, for example, be applied over the entire surface of the carrier layer or have channels, holes or other shaped openings. In the case of a discontinuous hydrogel layer, a multiplicity of discrete hydrogel elements can be applied to the carrier layer and / or to the absorbent layer, which elements can have the shape of circles, squares or other regular or irregular polygons.
  • the wound dressings also have a high level of comfort for the patient in that they are easy to use, skin-friendly, soft, thin, skin-conforming and analgesic (via a hydrogel cooling effect) and can therefore also be used over a long period of time, usually 3 to 5 days before changing the dressing.
  • the carrier material can be coated with an adhesive over the entire surface or partially, continuously or discontinuously.
  • a hydrogel according to the invention can be applied directly to a carrier layer. It can also be used with the help of an adhesive better cohesion. Further layers can be arranged between the carrier layer and the hydrogel layer. It has been found to be advantageous if a wound dressing has a layer as an additional layer which is capable of absorbing, storing and / or distributing liquid within the layer or transferring it to further layers. Suitable layers which are able to absorb liquids are nonwoven materials made of natural or synthetic fibers or mixtures thereof, open-pore foam materials or materials which contain a hydrophobic matrix in which particles which absorb liquids are contained. An open-cell foam material made of polyurethane is preferred.
  • a wound care product according to the invention preferably comprises a hydrophilic polyurethane foam.
  • a hydrophilic polyurethane foam is advantageous for rapid wound healing because such foams have a high absorption capacity and are therefore preferably used in the cleaning phase of wound healing in the case of heavy exudation.
  • Another advantage of polyurethane foams is that only low shear forces are exerted on a wound to be treated and the wound is thus well padded.
  • a hydrophilic polyurethane foam is understood to mean a polyurethane foam which can take up and store a liquid in its polyurethane matrix and in its pores, thus absorb it, and release at least part of the taken up liquid again.
  • Open-pored, hydrophilic polyurethane foams are particularly suitable as hydrophilic polymer foams.
  • a particularly preferred wound dressing comprises a layer which comprises an open-pored, hydrophilic polyurethane foam.
  • polyurethane foams should preferably be used which have a high absorption capacity for liquids of more than 2.5 g, preferably more than 10 g, even more preferably more than 16 g of isotonic salt solution per gram of foam polymer. The absorption capacity is determined according to DIN EN 13726-1: 2002 (3 min measurement). Such a foam can absorb germs and cell debris and safely enclose it, but still lie soft, supple and with a good cushioning effect on the wound.
  • the hydrophilic polyurethane foam preferably has an average pore size of less than 1000 ⁇ m, in particular 100 to 1000 ⁇ m, preferably 100 to 500 ⁇ m and very particularly preferably 100 to 300 ⁇ m.
  • the preferred method of determining pore size is to measure the diameter of a plurality of pores on one Section plane which is oriented parallel to the wound contact side of the foam layer or the wound care product. The measurement of the pore size can be done by looking at the pores in a light or electron microscope and comparing the pore diameter with a suitable scale.
  • the foam can have a homogeneous pore size or a gradient of the pore size over the thickness of the foam layer.
  • a reduction in the pore size starting from the wound contact layer from larger pores on the wound contact side (mean pore size e.g. 200-300 ⁇ m) to smaller pores on the one facing away from the wound during use Side of the foam (mean pore size, for example 100-200 ⁇ m) ensures efficient drainage of wound exudate.
  • An efficient drainage of wound exudate results because a capillary effect can be generated for particularly good absorption of liquids.
  • the foam can provide a sufficient amount of moisture for a wound.
  • a foam with a pore size gradient across the thickness of the foam and a pore size of less than 1000 ⁇ m is used, for example, in the product Permafoam from Paul Hartmann AG.
  • the wound dressing also has a water-vapor-permeable polyurethane cover layer.
  • the water vapor permeable polyurethane top layer has a water vapor permeability ("upright", measured according to DIN EN 13726-2 at a temperature of 37 ° C.) of more than 600 g / m 2 in 24 h.
  • the wound dressing has a reticulated hydrogel on the wound side. It is also advantageous if the wound dressing comprises a polyurethane cover layer away from the wound.
  • the foam has a density of 70 to 110 kg / m3.
  • a hydrophobic PU foam with a density of 10 to 50 kg / m 3 can be used.
  • foams are used in particular in wound dressings which are intended for negative pressure therapy of wounds.
  • silicone foams it would also be conceivable and advantageous to use silicone foams with a density of up to 300 kg / m 3.
  • Polyurethane foams are usually obtainable by reacting a curable mixture, comprising the components polyisocyanate and compounds reactive toward isocyanate, in particular polyol, as well as catalysts, blowing agents and optionally Additives.
  • a curable mixture comprising the components polyisocyanate and compounds reactive toward isocyanate, in particular polyol, as well as catalysts, blowing agents and optionally Additives.
  • polyisocyanate in particular polyo
  • diphenylmethane diisocyanate in particular 4,4'-diphenylmethane diisocyanate, mixtures of monomeric diphenylmethane diisocyanates and higher nuclear homologues of diphenylmethane diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, tolylene diisocyanate or mixtures thereof are suitable for producing the polyurethanes.
  • Isocyanate-reactive compounds are usually polyols such as polyetherols and / or polyesterols.
  • Foam wound dressings which comprise a polyurethane foam whose layer thickness is 0.1 cm to 1.8 cm, preferably from 0.3 cm to 1.5 cm and very particularly preferably from 0.5 cm to 1, have also been shown to be particularly advantageous designs. 0 cm.
  • the layer thickness can be the same at every point on the wound contact layer or assume different values in different areas of the wound contact layer.
  • the absorbent layer or the polyurethane foam has flattened edges.
  • the wound care product preferably has an essentially square basic shape. A size range of 8 cm x 8 cm up to 20 cm x 20 cm is particularly preferred.
  • the thickness of the wound care product is preferably less than 2 cm, the foam layer preferably having a thickness between 0.1 cm and 1.8 cm.
  • an additional material can be used as the wound contact layer.
  • a wound contact layer is in direct contact with the wound when the wound dressing according to the invention is used.
  • the only purpose of the wound contact layer is to space the foam away from the wound to be treated.
  • the additional layer has the advantage of ensuring that the wound care product is removed in a manner that is particularly gentle on the tissue when the dressing is changed.
  • the wound contact layer can perform further functions in relation to the wound to be treated.
  • the wound contact layer can supply the wound with moisture, have wound edge care properties, reduce skin irritation or have an antiadherent effect.
  • a wound dressing according to the invention can have a wound contact layer, the wound contact layer comprising a hydrogel, a polymer film, a hydrocolloid matrix, a polymer mesh, a nonwoven and / or an adhesive.
  • hydrogel or gel In the context of the invention, denotes a finely dispersed system composed of at least one solid and one liquid phase. This solid phase forms a spongy, three-dimensional network, the pores of which are filled by a liquid (lyogel) or a gas (xerogel). Both phases penetrate each other completely.
  • a hydrophilic polyurethane foam with a water content of at least 10 wt. Comprises% water, wherein the water can be released from the polymer foam or the polyurethane foam.
  • the proportion of water that may be used for formation is not to be understood. This water is covalently bound and is not available for wound treatment.
  • a proportion of water that is used for production reasons in the manufacture of the foam is also not to be understood.
  • a wound dressing according to the invention thus has a polymer foam or a polyurethane foam which comprises a water content which clearly exceeds a residual water content possibly caused by the production after drying.
  • a wound dressing according to the invention preferably comprises a hydrophilic polyurethane foam which has a retention value R of at least 20%. It is furthermore preferably provided here that the hydrophilic polyurethane foam has a retention value R of at least 30%, in particular of at least 40%, in particular at least 40% and very particularly preferably of at least 50%. Independently of this, it can furthermore preferably be provided that the wound dressing has a hydrophilic polyurethane foam which has a retention value R of at most 90%, in particular of at most 80% and very particularly of at most 70%. The retention value R is determined according to a method described herein.
  • a wound pad according to the invention very particularly preferably comprises a hydrophilic polyurethane foam which has a water content of at least 10% by weight, the water content corresponding to the retention value R of the polyurethane foam.
  • the hydrogel can be used in different ways to treat wounds.
  • the gel can be applied to the wound first and then covered with a wound pad.
  • Another possibility of using the gel for wound treatment is to use a wound dressing that holds the hydrogel in a wound contact layer. In this way, the pH stabilizing properties of the gel in the acidic range are provided in the wound.
  • Wound dressings that comprise a hydrogel matrix with a layer thickness of 0.1 to 5.0 mm have also been shown to be particularly advantageous embodiments.
  • a wound dressing according to the invention thus has a wound contact layer with a layer thickness of 0.1 to 5.0 mm, in particular 0.5 to 5.0 mm and very particularly preferably 0.5 to 3.0 mm.
  • Wound dressings with such layer thicknesses show, on the one hand, no wound adhesion and, on the other hand, the ability to absorb wound exudate released by a wound and to pass it on to the absorbent layer. These layer thicknesses can be the same at every point on the wound contact layer or assume different values in different areas of the wound contact layer.
  • the hydrogel matrix can preferably comprise channels, in particular conical channels, for the passage of liquids from the first to the second side.
  • channels in particular conical channels, for the passage of liquids from the first to the second side.
  • the channels have an elliptical or circular cross-section, ie that the channels have a circular or elliptical opening on both the first and the second side of the hydrogel matrix, the circular or elliptical opening on the first and the second side are of different sizes.
  • the channels have a triangular, rectangular, square, pentagonal, hexagonal or other polygonal cross section.
  • the first side has openings which are larger in comparison to the opening located on the second side.
  • the wound contact layer or the hydrogel matrix has openings which have a diameter of 0.5 to 5 mm.
  • the wound contact layer or the hydrogel matrix has openings which have a diameter of 1 to 3 mm.
  • the wound contact layer or the hydrogel matrix very particularly preferably has openings on the first side facing the wound that have a diameter of 1 to 3 mm have, wherein the second side of the wound contact layer or the hydrogel matrix is in direct contact with the polyurethane foam.
  • a transition layer is arranged between the absorbent layer and the wound contact layer.
  • a wound dressing according to the invention has a layer between the hydrogel matrix and polyurethane foam which comprises both materials.
  • this transition layer can have channels, openings or holes. If the transition layer has channels, openings or holes, according to a further preferred embodiment, these channels, openings or holes are filled with polyurethane foam. Furthermore, these channels, openings or holes are preferably congruent to the channels, openings or holes in the wound contact layer.
  • the hydrogels according to the invention are suitable for the treatment of wounds.
  • the present invention therefore also comprises hydrogels according to the invention for treating wounds.
  • the present invention comprises hydrogels for the treatment of chronic wounds such as pressure ulcers, pressure ulcers, pressure ulcers, venous leg ulcers, venous ulcers, arterial leg ulcers, arterial ulcers, wounds as a result of diabetic foot syndrome, neuropathic ulcers, but also wounds as a result of autoimmune diseases or from tumors (ulcerating tumors) or from radiation damage during tumor therapy.
  • Hydrogels or wound dressings according to the invention which contain them are suitable for phase-appropriate wound therapy, in particular for the therapy of wounds in the granulation phase and / or the epithelialization phase.
  • a first wound dressing (10) according to the invention is shown with a view of the wound contact layer.
  • the wound pad (10) is made as a so-called island dressing and consists of a carrier layer (11) made of a water-impermeable and water-vapor-permeable polyurethane film, which is coated over the entire surface with an acrylate adhesive (12).
  • an absorbent, hydrophilic polyurethane foam layer is applied by means of the acrylate adhesive (12) (not shown here), to which a hydrogel (15) according to the invention is applied as a wound contact layer.
  • the hydrophilic polyurethane foam layer has a water content of 40% by weight of water.
  • 100 g of a polyurethane foam used in this example comprises 40 g of water and 60 g of polyurethane matrix.
  • the hydrogel wound contact layer (15) is adhesively connected to the absorbent polyurethane foam layer (not shown here).
  • a multiplicity of circular holes (16) are made in the hydrogel wound contact layer in order to allow wound exudate to flow from the wound into the absorbent layer.
  • the hydrogel wound contact layer prevents newly formed cells from growing into the pores of the polyurethane foam.
  • the wound dressing (20) comprises a carrier layer (21) congruent with an absorbent layer (23) and made of a water-impermeable and water-vapor-permeable polyurethane foam, which is connected to the absorbent layer (23) by means of a discontinuous adhesive layer (22) made of an acrylate adhesive.
  • a discontinuous adhesive layer (22) made of an acrylate adhesive.
  • areas (27) of the absorbent layer and the carrier layer remain unconnected.
  • the wound pad comprises an absorbent layer (23) with a layer thickness of 4 mm and a carrier layer (21) with a layer thickness of 1.5 mm.
  • the absorbent layer (23) is formed from an open-pored hydrophilic polyurethane foam which has an average pore size of 220 ⁇ m.
  • the polyurethane foam has a water content of 70% by weight.
  • a hydrogel according to the invention is applied as a wound contact layer (25) to the first side of the polyurethane foam.
  • the hydrogel with a surface weight of 75 g / m 2 is not applied continuously to the polyurethane foam, so that circular holes (26) are provided in the hydrogel wound contact layer (25) for improved passage of wound exudate.
  • the polyurethane foam comprises a first side with an area of 25 cm 2 , the holes (26) occupying a total area of 5 cm 2.
  • the wound dressing (30) comprises a carrier layer (31) made of a water-impermeable and water vapor permeable polyurethane film, an absorbent layer (33) made of an open-pored hydrophilic polyurethane foam with a water content of 52.8% by weight (based on the polyurethane foam) and a wound contact layer (35) made of a hydrogel according to the invention with a water content of approx. 57.9 % By weight on (based on the hydrogel).
  • the carrier layer (31) is laminated over the entire surface to the hydrophilic polymer foam by means of an acrylate adhesive (32) applied to the polymer film.
  • a water-containing hydrogel (35) which comprises a polyurethane-polyurea copolymer, is applied to the first side of the absorbent layer, which faces the wound when in use.
  • the hydrogel wound contact layer is equipped with conical channels (36) with a circular cross-section (parallel to the wound) so that an improved wound exudate flow can take place from the wound into the absorbent hydrophilic foam (cf. Figure 3a ).
  • the still viscous hydrogel penetrated slightly into the polyurethane foam, so that a transition layer (34) consisting of the hydrogel and the hydrophilic polyurethane foam is formed between the hydrogel wound contact layer and the hydrophilic polyurethane foam.
  • the transition layer for its part, has channels (37) which are only filled with polyurethane foam and which are arranged congruently to the channels in the hydrogel wound contact layer.
  • the wound dressing (40) comprises a carrier layer (41) made of a water-impermeable and water-vapor-permeable polyurethane film, a layer (42) made of water-containing hydrogel according to the invention and a two-part cover layer (43) made of siliconized paper.
  • the hydrogel layer has a thickness of 3mm.
  • the masses of the constituents used in the reaction to produce the gels have the ratios given in Table 2 based on the total mass of the reactants used: Table 2: Mass ratios of the reactants used Example no. Jeffamin ED-2003 Aquapol PL- 13000-3 alcohol Demin.
  • Example No. 12 is a comparative example without polyhydric alcohol.
  • Example no. 13 is a comparative example according to WO2010 / 000451 .
  • moisture loss The loss of weight over a certain period of time at a defined temperature is described as moisture loss.
  • the term adhesive force describes the ability of an adhesive to adhere to a surface. It corresponds to the force that is necessary to detach a body that has come into contact with the gel surface from this surface and is determined with the aid of a static materials testing machine Zwick 010.
  • the gels must be conditioned under the test conditions for 24 hours before the test. For each measurement, three samples each with a size of 5 cm x 5 cm are punched out of the gels. The samples are attached to the side facing away from the wound with double-sided adhesive tape on a horizontally movable slide.
  • the approach speed of the slide is 100 mm / min, the contact time with the gel surface 2 s, the withdrawal speed of the slide 400 mm / min.
  • hydrogels were delivered sterile in Petri dishes.
  • 0.1 g / ml culture medium each of the samples was weighed out.
  • the cell activity, the number of cells and the protein concentration were examined three times per sample in four parallel batches each.
  • the elution time was 48 hours and the incubation of the cells with the eluates was also 48 hours.
  • DMEM Dulbecco's mod. Eagle Medium
  • VA BioLab 042901 was used as the culture medium for preculture and elution.
  • the cells were sown at a concentration of 50,000 cells / ml, preculturing took place at 37 ° C. and 5% CO2 for 24 h.
  • the DMEM medium added during sowing was then drawn off and the cells were each covered with 1 ml of eluate at a concentration of 100%.
  • DMEM medium was incubated for 48 h in a 50 ml Falcon tube like the samples; the eluate of the plastic discs in a concentration of 100% served as a positive control. After 48 hours of incubation, the cell activity, the number of cells and the total protein content were determined.
  • the cells were counted after enzymatic detachment of the cells by means of Accutase with the aid of the cell counter.
  • WST 1 tetrazolium salt
  • OD absorption values
  • the protein content is tested using the DC Protein Assay, from BIO-RAD GmbH Munich, according to the manufacturer's instructions.
  • the protein determination according to Lowry is based on the reduction of Cu (II) to Cu (I) by the aromatic tyrosine-tryptophan residues of proteins.
  • the copper-protein complex is reduced in a further step Phosphomolybdic acid phosphotungstate reagent for molybdenum or tungsten blue. The extinction of this intense blue color is measured photometrically at 750 nm.
  • the protein concentration can be determined by carrying a standard series.
  • a cell activity of 0-29% is characterized as a strongly reduced metabolic activity, a cell activity of 30-59% as a moderately reduced metabolic activity and a cell activity of 60-79% compared to the control as a weakly reduced metabolic activity.
  • Cell activity rates between 80 and 100% indicate a non-reduced metabolic activity.
  • a protein concentration of 0-34% is characterized as a strongly reduced protein content, and a protein concentration of 35-69% as a moderately reduced protein content compared to the control. Protein concentrations between 70 and 100% indicate a non-reduced protein content.
  • Table 5 Cell Compatibility Example no. sample Cell growth inhibition Decrease in metabolic activity Reduction in protein content 1 Glycerol 5% Weak Moderate Moderate 2 Glycerol 10% weak Weak No 3 Glycerol 15% Weak Weak No 4th Glycerol 20% Weak Weak No 5 Glycerol 25% Weak Weak No 6th Glycerol 30% moderate weak no 7th Ethylene glycol 20% Moderate moderate Moderate 8th Sorbitol 20% Moderate strong Moderate 9 Sucrose 20% Weak moderate No 10 PEG300 20% strong Strong Moderate 11 PEG2000 20% moderate moderate Moderate 12th H2O weak weak Moderate 13th Propylene glycol 20% Strong Strong Moderate

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DE102018102126A1 (de) * 2018-01-31 2019-08-01 Lohmann & Rauscher Gmbh & Co. Kg Wundauflage
DE102019128569A1 (de) * 2019-10-23 2021-04-29 Julius-Maximilians-Universität Würzburg Wundauflage umfassend eine Wundkontaktschicht mit einer bahnförmigen Beschichtung für eine gerichtete Zellmigration
DE102020134827A1 (de) * 2020-12-23 2022-06-23 Paul Hartmann Ag Hydrogel zur Behandlung von Druckgeschwüren
WO2022226857A1 (zh) * 2021-04-29 2022-11-03 美丽康生技股份有限公司 一种用于刺青护色的湿式敷料及其使用方法
DE102021118759A1 (de) * 2021-07-20 2023-01-26 Paul Hartmann Ag Strahlenvernetzung und Sterilisation von Silicon
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AU622935B2 (en) * 1988-09-26 1992-04-30 Paul Hartmann Ag Wound dressing
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